A method for preparing benzoic acid intermediate and intermediate thereof

Abstract

The present invention discloses a method for preparing a phenylephrine intermediate and the intermediate. The method comprises the following steps: reacting compound 1 with 1,4-dibromobutane in a solvent in the presence of a base to obtain compound 2, as shown below. The method utilizes safe reagents, is simple to operate, has low production costs, and produces a high yield and purity of the resulting product, making it suitable for large-scale industrial production. #imgabs0#

Description

Technical Field

[0001] The present invention relates to a preparation method of a phenylepicric acid intermediate and the intermediate. Background Art

[0002] Bempedoic acid, developed by Esperion Therapeutic, is a novel small molecule compound for treating dyslipidemia and reducing the risk of other cardiovascular diseases. Compared to statins, which are currently widely used clinically, bempedoic acid has the advantage of being well-tolerated and, when used in combination with statins, can be used to treat LDL-C levels that are uncontrolled by existing methods. Bempedoic acid is the first non-statin oral cholesterol-lowering drug approved by the FDA in nearly 20 years. Its structural formula is as follows:

[0003]

[0004] The synthesis method of phenylephrine reported in WO2004067489 is shown in Scheme 1:

[0005]

[0006] The p-methylbenzenesulfonylmethyl isocyanide used in this process second step is highly toxic and has poor atom economy. In addition, sodium hydride, a hazardous chemical, is used. Sodium hydride can spontaneously combust in moist air, is heated or contacts with moisture or acids, and releases heat and hydrogen, causing combustion and explosion, which is unfavorable for industrial production operation. Potential genotoxic impurity A (p-methylbenzenesulfonyl derivative) will be produced after the third step hydrolysis, which is unfavorable for the quality control of bulk drug. In addition, the purification of intermediate compound 3 also needs to use column chromatography. The yield of each step reaction is low, and reaction conditions are relatively harsh, so this route is not suitable for industrialized large-scale production.

[0007] The synthesis method reported in CN111170855A is shown in Scheme 2:

[0008]

[0009] This route uses isobutyrate as the starting material, which undergoes alkylation with a 1,4-dihaloalkane to produce compound 1. Compound 1 is then condensed with acetone dicarboxylic acid diester to produce compound 2. Compound 2 is then hydrolyzed in an ethanolic environment and acidified to produce compound 3. Finally, it is reduced with sodium borohydride to produce benzoic acid. The second condensation step in this route suffers from selectivity and multiple substitution issues, resulting in low yields. Consequently, this route suffers from low overall yields and demanding reaction conditions.

[0010] The synthesis method reported in CN111825546A is shown in Scheme 3:

[0011]

[0012] WO2020141419 reports four synthesis methods, of which the second method also uses the toxic reagent p-methylphenylsulfonylmethyl isocyanide, and the fourth method is similar to CN111170855A. The first and third synthesis methods are shown in Scheme 4 and Scheme 5, respectively:

[0013]

[0014] Both Route 4 and Route 5 require the use of ethyl 6-bromo-2,2-dimethylhexanoate, which requires distillation for purification.

[0015] Therefore, how to develop a benzoic acid synthesis process that is simple and safe to operate, has low production cost, and has high yield and quality is a technical problem that the present invention urgently needs to solve. Summary of the Invention

[0016] The present invention aims to address the technical problems of prior art methods for preparing phenylepicric acid intermediates, which have the disadvantages of requiring highly toxic and explosive reagents, long routes, low yields, and unsuitability for large-scale industrial production. The present invention provides a method for preparing a phenylepicric acid intermediate and the intermediates thereof. The preparation method of the present invention utilizes safe reagents, is simple to operate, has low production costs, and produces a high yield and purity of the obtained product, thus facilitating large-scale industrial production.

[0017] The present invention solves the above technical problems through the following technical solutions.

[0018] The present invention provides a method for preparing compound 2, comprising the following steps: in a solvent, under the action of a base, reacting compound 1 with 1,4-dibromobutane to obtain compound 2 as shown below;

[0019]

[0020] In the preparation method of compound 2, the reaction methods and conditions shown can be conventional in the art, and the following methods and conditions are preferred:

[0021] The solvent is an ether solvent, preferably tetrahydrofuran and / or diethyl ether, for example, anhydrous tetrahydrofuran. The volume molar ratio of the solvent to compound 1 is 2.0 to 4.0 L / mol, for example, 2.88 L / mol.

[0022] The base is lithium diisopropylamide. The molar ratio of the base to compound 1 is 1.0 to 1.5, for example, 1.20.

[0023] The addition temperature of the alkali is -10 to 0°C.

[0024] The molar ratio of 1,4-dibromobutane to compound 1 is 1.0 to 1.5, for example, 1.20.

[0025] The progress of the reaction can be monitored by conventional monitoring methods in the art (eg, TLC, HPLC, or NMR), and the reaction endpoint is generally determined when the content of compound 1 no longer changes. The reaction time is 2 to 5 hours.

[0026] The reaction may further include post-treatment. The post-treatment method is a conventional post-treatment method for this type of reaction, preferably comprising the following steps: quenching the reaction, separating the liquids, washing the organic phase with saturated brine, concentrating, and adding n-hexane for crystallization to obtain Compound 2.

[0027] The preparation method of compound 2 may further comprise the following steps:

[0028] Method 1: In a solvent, in the presence of a condensing agent, triphenylmethanol and isobutyric acid are subjected to a condensation reaction as shown below to obtain compound 1;

[0029]

[0030] Alternatively, method 2: In a solvent, in the presence of an acid-binding agent, triphenylmethane and isobutyric acid are subjected to a condensation reaction as shown below to obtain compound 1;

[0031]

[0032] In method 1, the reaction method and conditions can be conventional methods and conditions for such reactions in the art, and the following methods and conditions are preferred:

[0033] The solvent is a halogenated hydrocarbon solvent, preferably dichloromethane. The volume molar ratio of the solvent to triphenylmethanol is 2.0 to 4.0 L / mol, for example, 2.7 L / mol.

[0034] The condensing agent is one or more of DIC, DCC and EDCI. The molar ratio of the condensing agent to triphenylmethanol is 1.0 to 1.5, for example, 1.2.

[0035] The adding temperature of the condensing agent is 0-10°C.

[0036] The molar ratio of isobutyric acid to triphenylmethanol is 1.0 to 1.5, for example, 1.1.

[0037] The reaction temperature is room temperature.

[0038] The progress of the reaction can be monitored by conventional monitoring methods in the art (such as TLC, HPLC or NMR), and the reaction endpoint is generally when the content of triphenylmethanol no longer changes. The reaction time is 5 to 8 hours.

[0039] The reaction may further include post-treatment. The post-treatment may adopt conventional post-treatment methods for this type of reaction, preferably comprising the following steps: filtering, washing the filtrate with saturated sodium bicarbonate aqueous solution and water in sequence, drying, and concentrating to obtain Compound 1.

[0040] In method 2, the reaction method and conditions can be conventional methods and conditions for such reactions in the art, and the following methods and conditions are preferred:

[0041] The solvent is a halogenated hydrocarbon solvent, preferably dichloromethane. The volume molar ratio of the solvent to triphenylmethane is 2.0 to 4.0 L / mol, for example, 2.7 L / mol.

[0042] The acid binding agent is triethylamine and / or DIPEA. The molar ratio of the acid binding agent to triphenylmethane is 1.0 to 1.5, for example, 1.1.

[0043] The molar ratio of isobutyric acid to triphenylmethane is 1.0 to 1.5, for example, 1.1.

[0044] The reaction temperature is room temperature.

[0045] The progress of the reaction can be monitored by conventional monitoring methods in the art (such as TLC, HPLC or NMR), and the reaction endpoint is generally determined when the content of triphenylmethane no longer changes. The reaction time is 6 to 12 hours.

[0046] The reaction may further include post-treatment. The post-treatment may adopt conventional post-treatment methods for this type of reaction, preferably comprising the following steps: filtering, washing the filtrate with saturated sodium bicarbonate aqueous solution and water in sequence, drying, and concentrating to obtain Compound 1.

[0047] The present invention also provides a method for preparing compound 3, which comprises the following steps: in a solvent, in the presence of an initiator and magnesium, reacting compound 2 with 1,3-dibromo-2,2-dimethoxypropane to obtain compound 3;

[0048]

[0049] The preparation method of the compound 3 may further comprise the following steps: obtaining the compound 2 according to the preparation method of the compound 2.

[0050] In the preparation method of compound 3, the reaction method and conditions can be conventional in the art, and the following methods and conditions are preferred:

[0051] The solvent is an ether solvent, preferably tetrahydrofuran and / or diethyl ether, for example, anhydrous tetrahydrofuran. The volume molar ratio of the solvent to 1,3-dibromo-2,2-dimethoxypropane is 4.0 to 7.0 L / mol, for example, 5.2 L / mol.

[0052] The initiator is iodine, and the amount of the initiator used is a catalytic amount, for example, one grain of iodine or 0.001 equivalent.

[0053] The magnesium is magnesium powder or magnesium chips. The molar ratio of magnesium to 1,3-dibromo-2,2-dimethoxypropane is 2.0-3.0, for example, 2.33.

[0054] The molar ratio of the compound 2 to 1,3-dibromo-2,2-dimethoxypropane is 2.0-3.0, for example, 2.33.

[0055] The preparation method of compound 3 comprises the following steps: mixing magnesium and a small amount of 1,3-dibromo-2,2-dimethoxypropane in a solvent, heating the mixture to 40°C, adding the initiator, and slowly adding the remaining 1,3-dibromo-2,2-dimethoxypropane dropwise after reflux or significant heat release. After the addition is complete, the mixture is refluxed and reacted until the magnesium content in the system no longer changes. The mixture is then cooled to 0-10°C, compound 2 is added, and the reaction is continued at this temperature.

[0056] The reaction is carried out under gas protection, preferably nitrogen and / or argon.

[0057] The progress of the reaction can be monitored by conventional monitoring methods in the art (eg, TLC, HPLC, or NMR), and the reaction endpoint is generally determined when the content of compound 2 no longer changes. The reaction time is preferably 5 to 8 hours, for example, 6 hours.

[0058] The reaction may also include post-treatment. Conventional post-treatment methods for this type of reaction can be used for this post-treatment, preferably including the following steps: quenching the reaction at 0-10°C, extracting, drying, and concentrating to obtain a crude product. The crude product is heated to 50°C in a 1:1 volume ratio of n-hexane to methyl tert-butyl ether until dissolved, cooled to -10°C, and a solid precipitated. The solid is filtered and dried to obtain compound 3.

[0059] The present invention also provides a method for preparing compound 4, which comprises the following steps: in a solvent, under the action of an acid, subjecting compound 3 to a hydrolysis reaction as shown below to obtain compound 4;

[0060]

[0061] The preparation method of the compound 4 may further comprise the following steps: obtaining the compound 2 according to the preparation method of the compound 3.

[0062] In the preparation method of compound 4, the solvent can be a conventional solvent for this type of hydrolysis reaction in the art, preferably a mixed solvent of an ether solvent and water. The ether solvent is preferably one or more of methyl tert-butyl ether, tetrahydrofuran, and diethyl ether. In the mixed solvent, the volume ratio of the ether solvent to water is preferably 1.0 to 2.0, for example, 1.67.

[0063] In the preparation method of compound 4, the amount of the solvent used can be the conventional amount used in the art for this type of hydrolysis reaction, as long as compound 3 is dissolved. Preferably, the volume molar ratio of the solvent to compound 3 is 3.0 to 6.0 L / mol, for example, 7.02 L / mol.

[0064] In the preparation method of compound 4, the acid can be a conventional acid used in the art for this type of hydrolysis reaction, preferably an inorganic acid, more preferably hydrochloric acid and / or sulfuric acid, for example, 36% concentrated hydrochloric acid. The amount of the acid used can be a conventional amount used in the art for this type of reaction, and the solution formed by the acid and the mixed solvent preferably has a pH of 2 to 5, more preferably a pH of 3 to 4.

[0065] In the preparation method of compound 4, the reaction temperature is a conventional temperature for this type of reaction, preferably 0°C to 10°C.

[0066] In the preparation method of compound 4, the reaction progress can be monitored by conventional monitoring methods in the art (such as TLC, HPLC or NMR), and the reaction endpoint is generally the disappearance of compound 3. The reaction time is preferably 0.5 to 1.0 hour.

[0067] In the preparation method of compound 4, the reaction may further include post-treatment, which is a conventional post-treatment method for this type of reaction, preferably comprising the following steps: adjusting the pH of the solution to 8-9, separating the liquids, adjusting the pH of the resulting aqueous phase to 2-3, extracting with an organic solvent, concentrating, and recrystallizing the residue. The recrystallization solvent is preferably methyl tert-butyl ether and n-hexane in a volume ratio of 1:5.

[0068] Alternatively, the present invention provides a method for preparing compound 4, comprising the following steps:

[0069] (1) In a solvent, in the presence of a condensing agent, triphenylmethanol and isobutyric acid are subjected to a condensation reaction as shown below to obtain compound 1; alternatively, in a solvent, in the presence of an acid-binding agent, triphenylmethane and isobutyric acid are subjected to a condensation reaction as shown below to obtain compound 1;

[0070] (2) In a solvent, under the action of a base, compound 1 is reacted with 1,4-dibromobutane to obtain compound 2 as shown below;

[0071] (3) Under the action of an initiator and magnesium, compound 2 is reacted with 1,3-dibromo-2,2-dimethoxypropane to obtain compound 3 as shown below;

[0072] (4) In a solvent, under the action of an acid, compound 3 is hydrolyzed to obtain compound 4;

[0073]

[0074] The present invention provides an intermediate of benzoic acid, the structure of which is shown below:

[0075]

[0076] In the present invention, the room temperature is -10 to 35°C, preferably 10 to 30°C.

[0077] In the present invention, the DIC is 1,3-diisopropylcarbodiimide; the DCC is dicyclohexylcarbodiimide; the EDCI is 1-ethyl-3 (3-dimethylpropylamine) carbodiimide hydrochloride; and the DIPEA is N,N-diisopropylethylamine.

[0078] Without violating the common sense in the art, the above-mentioned preferred conditions can be arbitrarily combined to obtain preferred embodiments of the present invention.

[0079] The reagents and raw materials used in the present invention are commercially available.

[0080] The positive progress of the present invention is that the reagents used in the preparation method are safe, the operation is simple, the production cost is low, the yield and purity of the obtained product are high, and it is conducive to large-scale industrial production. DETAILED DESCRIPTION

[0081] Example 1 Preparation of Compound 1

[0082] To a three-necked reaction flask, add 78.0 g (0.30 mol) of triphenylmethanol, 29.0 g (0.33 mol) of isobutyric acid, and 810 mL of dichloromethane and stir. Cool to 0-10°C and add 41.1 g (0.36 mol) of DIC (1,3-diisopropylcarbodiimide) dropwise under temperature control. After completion of the addition, warm to room temperature and continue stirring for 5-8 hours. Follow TLC until the reaction is complete. Filter and wash the filtrate with 300 mL of saturated sodium bicarbonate solution and then 300 mL of water. Concentrate the organic layer and dry to obtain 96.1 g of a crystalline solid. Yield: 97.1%. HPLC purity: 98.5%. ESI-MS (m / Z): 331.26 [M+H] + .

[0083] Example 2 Preparation of Compound 1

[0084] At room temperature, 83.6 g (0.30 mol) of triphenylmethane was added portionwise to a mixture of 29.0 g (0.33 mol) of isobutyric acid and 33.3 g (0.33) of triethylamine in 810 mL of dichloromethane. The mixture was stirred at room temperature overnight. TLC was performed until the reaction was complete. The mixture was washed with 300 mL of saturated sodium bicarbonate solution and 300 mL of water. The organic layer was concentrated and dried to give 98.1 g of a crystalline solid with HPLC purity of 98.5% and a yield of 96.9%. ESI-MS (m / Z): 331.26 [M+H] + .

[0085] Example 3 Preparation of Compound 2

[0086] To a three-necked flask, add 179.2 g (0.24 mol) of compound 1,4-dibromobutane (62.6 g (0.29 mol)), and tetrahydrofuran (690 mL) with stirring. Cool to -10-0°C, and under temperature control, add 144 mL (0.29 mol) of 2N lithium diisopropylamide dropwise. Continue the reaction for 2-5 hours. TLC indicates that the starting material has essentially reacted completely, and quench the reaction by adding 300 mL of water. Adjust the pH to 6-7 with 2N hydrochloric acid, and separate the layers. Wash the organic layer with 150 mL of saturated sodium chloride solution twice. Concentrate to dryness, add 180 mL of n-hexane to the residue, and stir rapidly. Filter and dry to obtain 94.9 g of a white solid (yield: 85.0%), HPLC purity: 98.2%, ESI-MS (m / Z): 487.23 [M+Na]. + ;1H NMR(CDCl3,400MHz)δH 7.29 (d,3H),7.28(d,6H),7.27(dd,6H),3.53(t,2H),1.83(m,2H),1.64(t,2H),1.30(m,2H),1.28(s,6H).

[0087] Example 4 Preparation of Compound 3

[0088] Under nitrogen, add 3.4 g (0.14 mol) of magnesium powder to 130 mL of anhydrous tetrahydrofuran, followed by 2.6 g (0.01 mol) of 1,3-dibromo-2,2-dimethoxypropane. Raise the temperature to 30-40°C and add one iodine pellet to initiate the reaction. After the exotherm subsides, raise the temperature to 50-60°C and slowly add 13.0 g (0.05 mol) of 1,3-dibromo-2,2-dimethoxypropane dropwise until the magnesium powder is largely dissolved. Continue the reaction at this temperature for 4 hours, or until the reaction system becomes a gray-brown, thick, viscous liquid. Cool the temperature to 0-10°C and add a solution of compound 265.0 g (0.14 mol) dissolved in 130 mL of anhydrous tetrahydrofuran dropwise. Continue the reaction at this temperature for 6 hours. TLC was followed until the majority of the starting material had reacted completely. The reaction was quenched by adding 50 mL of saturated aqueous ammonium chloride solution, maintaining the temperature at 0-10°C. Extraction was performed with 200 mL of n-hexane (2 x 2), and the mixture was dried over anhydrous magnesium sulfate. The mixture was filtered and concentrated to dryness. 40 mL of n-hexane and 40 mL of methyl tert-butyl ether were added to the residue, and the temperature was raised to 45-50°C with stirring to dissolve the residue. The mixture was cooled to -10-0°C and crystallized. The mixture was filtered and dried under vacuum at 40°C to yield 43.9 g of a white solid with an HPLC purity of 97.8% and a yield of 82%. ESI-MS (m / Z): 873.4 [M+H]. + ; 1 HNMR(CDCl3,400MHz)δH7.29(d,6H), 7.28(d,12H),7.27(dd,12H),3.35(s,6H),1.62(t,6H),1.52(t,6H),1.30(m,8H),1.29(s,12H),1.27(m,4H).

[0089] Example 5 Preparation of Compound 3

[0090] Under nitrogen, add 10.7 g (0.44 mol) of magnesium powder to 400 mL of anhydrous tetrahydrofuran, followed by 5.2 g (0.02 mol) of 1,3-dibromo-2,2-dimethoxypropane. Raise the temperature to 30-40°C and add 227 mg (0.18 mmol) of iodine to initiate the reaction. After the exotherm ends, raise the temperature to 50-60°C and slowly add 42.0 g (0.16 mol) of 1,3-dibromo-2,2-dimethoxypropane dropwise until the magnesium powder is mostly dissolved. Continue the reaction at this temperature for 4 hours, or until the reaction system becomes a gray-brown, viscous liquid. Cool the temperature to 0-10°C and add a solution of 186.0 g (0.40 mol) of compound 2 dissolved in 260 mL of anhydrous tetrahydrofuran dropwise. Continue the reaction at this temperature for 6 hours. TLC was followed until the majority of the starting material had reacted completely. The temperature was maintained at 0-10°C, and the reaction was quenched by adding 100 mL of saturated aqueous ammonium chloride. The product was extracted with 2 400 mL of n-hexane and dried over anhydrous magnesium sulfate. Filtered and concentrated to dryness, the residue was added with 120 mL of n-hexane and 120 mL of methyl tert-butyl ether, and the temperature was raised to 45-50°C with stirring to dissolve the concentrated residue. The temperature was lowered to -10-0°C and crystallized. Filtered and dried under vacuum at 40°C to obtain 137.4 g of a white solid, with a yield of 85% and a HPLC purity of 97.2%. ESI-MS (m / Z): 873.4 [M+H]. + .

[0091] Example 6 Preparation of Compound 4

[0092] Compound 3 (36.0 g, 0.041 mol) was dissolved in 180 mL of methyl tert-butyl ether (MTBE). 108 mL of water was added, and the mixture was cooled to 0-10°C. Concentrated hydrochloric acid was added to adjust the pH to 3-4. The mixture was stirred at this temperature for 30 minutes, and the pH was adjusted to 8-9 with a 10% aqueous sodium hydroxide solution. The organic layer was separated, and 18.2 g of triphenylmethanol was recovered by concentration. The aqueous layer was adjusted to pH 2-3 with concentrated hydrochloric acid, and extracted with 180 mL of MTBE. The organic layer was separated, and concentrated to dryness. The residue was added to a mixed solvent of MTBE:n-hexane = 1:5 (v:v), and the temperature was raised to 50-60°C to dissolve the residue. The mixture was cooled to -10-0°C and crystallized. Filtered, the mixture was dried under vacuum at 40°C to obtain 12.2 g of an off-white solid (87% yield). The HPLC purity was 99.6% (200 nm). ESI-MS (m / Z): 343.25 [M+H]. + .

Claims

1. A method for preparing compound 3, characterized in that: The method comprises the following steps: in a solvent, under the action of an initiator and magnesium, reacting compound 2 with 1,3-dibromo-2,2-dimethoxypropane to obtain compound 3; 2. The preparation method according to claim 1, wherein The preparation method of compound 2 comprises the following steps: in a solvent, under the action of a base, reacting compound 1 with 1,4-dibromobutane as shown below to obtain compound 2; 3. The preparation method according to claim 2, wherein In the preparation method of compound 2, The solvent is an ether solvent; and / or, the volume molar ratio of the solvent to compound 1 is 2.0 to 4.0 L / mol; The base is lithium diisopropylamide; and / or, the molar ratio of the base to compound 1 is 1.0 to 1.5; And / or, the base is added at a temperature of -10 to 0°C.

4. The preparation method according to claim 3, wherein The solvent is tetrahydrofuran and / or ether.

5. The preparation method according to claim 2, wherein: The preparation method of compound 1 comprises the following steps: Method 1: in a solvent, in the presence of a condensing agent, triphenylmethanol and isobutyric acid are subjected to a condensation reaction as shown below to obtain compound 1; Alternatively, method 2: in a solvent, in the presence of an acid-binding agent, triphenylmethane and isobutyric acid are subjected to a condensation reaction as shown below to obtain compound 1; 6. The preparation method according to claim 5, wherein In the preparation method of compound 1, In method 1, the solvent is a halogenated hydrocarbon solvent; And / or, in method 1, the volume molar ratio of the solvent to triphenylmethanol is 2.0 to 4.0 L / mol; And / or, in method 1, the condensing agent is one or more of DIC, DCC and EDCI; And / or, in method 1, the molar ratio of the condensing agent to triphenylmethanol is 1.0 to 1.5; And / or, in method 1, the condensing agent is added at a temperature of 0 to 10°C; And / or, in method 1, the molar ratio of isobutyric acid to triphenylmethanol or triphenylmethane is 1.0 to 1.5; And / or, in method 1, the reaction temperature of the reaction is room temperature; And / or, in method 2, the solvent is a halogenated hydrocarbon solvent; And / or, in method 2, the volume molar ratio of the solvent to triphenylmethane is 2.0 to 4.0 L / mol; And / or, in method 2, the acid binding agent is triethylamine and / or DIPEA; And / or, in method 2, the molar ratio of the acid binding agent to triphenylmethane is 1.0 to 1.5; And / or, in method 2, the molar ratio of isobutyric acid to triphenylmethane is 1.0 to 1.5; And / or, in method 2, the reaction temperature is room temperature.

7. The preparation method according to claim 6, wherein In method 1, the solvent is dichloromethane; And / or, in method 2, the solvent is dichloromethane; 8. The preparation method according to claim 1, wherein The solvent is an ether solvent; and / or, the volume molar ratio of the solvent to 1,3-dibromo-2,2-dimethoxypropane is 4.0 to 7.0 L / mol; and / or, the initiator is iodine; And / or, the amount of the initiator is a catalytic amount; And / or, the magnesium is magnesium powder or magnesium chips; and / or, the molar ratio of magnesium to 1,3-dibromo-2,2-dimethoxypropane is 2.0 to 3.0; and / or, the molar ratio of the compound 2 to 1,3-dibromo-2,2-dimethoxypropane is 2.0 to 3.0; And / or, the preparation method of the compound 3 comprises the following steps: mixing magnesium and a small amount of 1,3-dibromo-2,2-dimethoxypropane in a solvent, heating to 40°C, adding the initiator, and slowly adding the remaining 1,3-dibromo-2,2-dimethoxypropane dropwise after reflux or obvious heat release. After the addition is complete, reflux reaction is carried out until the magnesium content in the system no longer changes, cooling to 0-10°C, adding compound 2, and maintaining this temperature to carry out the reaction; And / or, the reaction is carried out under gas protection.

9. The preparation method according to claim 8, wherein The solvent is tetrahydrofuran and / or ether.

10. A method for preparing compound 4, characterized in that: The method comprises the following steps: in a solvent, under the action of an acid, subjecting compound 3 to a hydrolysis reaction as shown below to obtain compound 4; 11. The preparation method according to claim 10, characterized in that The method may further comprise the following steps: obtaining the compound 3 according to the preparation method of the compound 3 according to any one of claims 1 to 9; And / or, the solvent is a mixed solvent of an ether solvent and water; and / or, the volume molar ratio of the solvent to compound 3 is 3.0 to 6.0 L / mol; and / or, the acid is an inorganic acid; and / or, the pH of the solution formed by the acid and the mixed solvent is 2 to 5; And / or, the reaction temperature of the reaction is 0°C to 10°C.

12. The preparation method according to claim 11, characterized in that When the solvent is a mixed solvent of an ether solvent and water, the ether solvent is one or more of methyl tert-butyl ether, tetrahydrofuran and diethyl ether; And / or, when the solvent is a mixed solvent of an ether solvent and water, the volume ratio of the ether solvent to water is 1.0 to 2.0; and / or, when the acid is an inorganic acid, the acid is hydrochloric acid and / or sulfuric acid; And / or, the pH of the solution formed by the acid and the mixed solvent is 3-4.

13. An intermediate of benzoic acid, the structure of which is shown below:

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